RNA Polymerase 1-driven Transcription as a Mediator of BDNF-induced Neurite Outgrowth

• Published in: The Journal of biological chemistry Vol. 286; no. 6; pp. 4357 - 4363
• Main Authors: Gomes, Cynthia, Smith, Scott C., Youssef, Mark N., Zheng, Jing-Juan, Hagg, Theo, Hetman, Michal
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.02.2011; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Brain-Derived Neurotrophic Factor - metabolism; Brain-Derived Neurotrophic Factor - pharmacology; Cell Nucleolus - genetics; Cell Nucleolus - metabolism; Cells, Cultured; Enzyme Activation - drug effects; Enzyme Activation - physiology; ERK; Hippocampus - cytology; Hippocampus - metabolism; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; MAP Kinases (MAPKs); Mitogen-Activated Protein Kinase 3 - metabolism; Neurites - metabolism; Neurobiology; Neurodevelopment; Neurodifferentiation; Neurotrophic Factor; Neurotrophin; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Nucleolus; Prosencephalon - cytology; Prosencephalon - metabolism; Rats; Rats, Sprague-Dawley; Ribosomal RNA (rRNA); RNA Polymerase I - genetics; RNA Polymerase I - metabolism; RNA Polymerase-1; Transcription; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic - drug effects; Transcription, Genetic - physiology; Neurotrophin; Ribosomal RNA (rRNA); MAP Kinases (MAPKs); Neurodifferentiation; RNA Polymerase-1; Transcription; Neurodevelopment; Nucleolus; Neurotrophic Factor; ERK
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.170134

Neurite outgrowth is essential for development of the nervous system. Neurotrophins including BDNF are among extracellular signals that regulate neurite outgrowth. The ERK1/2 pathway contributes to intracellular signaling networks transducing the pro-neuritic effects of BDNF. In the nucleolus, RNA polymerase-1 (Pol1)-mediated transcription regulates ribosomal biogenesis, enabling cellular protein synthesis and growth. Hence, we tested the possibility that Pol1 is an effector for pro-neuritic signals such as BDNF. We report that Pol1-mediated nucleolar transcription was increased by BDNF in an ERK1/2-dependent manner in rat forebrain neurons. Conversely, in cultured hippocampal neurons, knockdown of a Pol1 coactivator, transcription initiation factor 1A (TIF1A), attenuated BDNF- or ERK1/2-induced neurite outgrowth. Also, upon overexpression, a constitutively active mutant of TIF1A strongly promoted neurite outgrowth, including increases in total neurite length and branching. Finally, overexpression of wild-type TIF1A enhanced the pro-neuritic effects of ERK1/2 activation. These observations indicate that the Pol1-mediated nucleolar transcription regulates neurite outgrowth and serves as a major pro-neuritic effector of the BDNF-activated ERK1/2 pathway. Thus, development of the nervous system appears critically dependent on the nucleolus.